Extended Data Fig. 6: Proposed mechanisms of Syk signaling, inhibition, and resistance in AML cells.
From: Targeting lipid–protein interaction to treat Syk-mediated acute myeloid leukemia
a. In the resting state, Syk is autoinhibited by intramolecular tethering by interdomain A (ID-A; dark red) and B (ID-B) which occludes the kinase (Kin) domain. b. IgG2-activated FcγRI causes the associated ITAM motif to be doubly phosphorylated (pY2-ITAM) by a Src family kinase, creating a docking site for Syk. c. Recruitment of Syk to the activated receptor requires coincident Syk-cSH2-PIP3 binding and Syk-n/cSH2-pY2-ITAM binding, which leads to conformational changes and activation of Syk. d. WC36 specifically blocks this process by inhibiting Syk-cSH2-PIP3 binding while entospletinib cannot. e. Once activated by the receptor, Syk typically undergoes autophosphorylation (pY: green) of ID-A and ID-B for sustained activation and functions as both a kinase and a scaffolding protein. As a kinase, Syk phosphorylates a constitutively active FLT3 mutant (for example, FLT3-ITD), which is essential for AML cell proliferation. Activated Syk also serves as a scaffolding protein for FLT3, RAS-RAF-MEK-ERK and STA3/5 either directly or via an adaptor protein (for example, X = KSR). f. Entospletinib can block the kinase activity of Syk but cannot inhibit the scaffolding function, allowing the AML cells to develop acquired resistance mechanism that bypasses the Syk kinase activity. WC36 does not allow any type of resistance because it blocks all functions of Syk at the source.
